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OBJECTIVE--This study assesses β-cell replication in human donor organs and examines possible influences of the preterminal clinical conditions. RESEARCH DESIGN AND METHODS--β-Cell replication was quantified in a consecutive series of n = 363 human organ donors using double immunohistochemistry for Ki67 and insulin. Uni- and multivariate analysis was used to correlate replication levels to clinical donor characteristics and histopathologic findings. RESULTS--β-Cell replication was virtually absent in most donors, with ≤ 0.1% Ki67-positive β-cells in 72% of donors. A subpopulation of donors, however, showed markedly elevated levels of replication of up to 7.0% Ki67-positive β-cells. β-Cell replication was accompanied by the increased replication of glucagon-, somatostatin-, and CA19.9-positive cells. Prolonged life support, kidney dysfunction, relatively young donor age, inflammatory infiltration, and prolonged brain death before organ retrieval were all found to be significantly associated with an increased level (≥ 90th percentile) of β-cell replication, with the first three risk factors being independent predictors. Increased β-cell replication was most often noted in relatively young donors (≤ 25 years) who received prolonged (≥ 3 days) life support (68%); in contrast, it was rare in donors with a short duration of life support regardless of age (1%). Prolonged life support was accompanied by increased levels of [CD68.sub.+] and LCA/[CD45.sup.+] infiltration in the pancreatic parenchyma. CONCLUSION--These results indicate that preterminal clinical conditions in (young) organ donors can lead to increased inflammatory infiltration of the pancreas and to increased β-cell replication. Diabetes 59:1702-1708, 2010, Human diabetes is a heterogeneous group of disorders with increased glycemia levels and a decreased functional β-cell mass in common. Type 1A diabetes is characterized by a T-cell-mediated autoimmune destruction [...]

Antibodies against islet cell antigens are used as predictive markers of type 1 diabetes, but it is unknown whether they reflect an ongoing autoimmune process in islet tissue. We investigated [...]

Use of sulfonylureas in diabetes treatment is based on their insulin-releasing effect on pancreatic β-cells. Prolonged action is known to degranulate β-cells, but functional consequences have not been examined at the cellular level. This study investigates influences of in vivo (48-h) and in vitro (24-h) glibenclamide treatment on the functional state of the β-cell population. Both conditions decreased cellular insulin content by >50% and caused an elevated basal insulin biosynthetic activity that was maintained for at least 24 h after drug removal. Glibenclamide stimulation of basal insulin synthesis was not achieved after a 2-h exposure; it required a calcium-dependent translational activity and involved an increase in the percent activated β-cells (50% after glibenclamide pretreatment vs. 8% in control cells). The glibenclamide-activated β-cell subpopulation corresponded to the degranulated β-cell subpopulation that was isolated by fluorescence-activated cell sorter on the basis of lower cellular sideward scatter. Glibenclamide pretreatment did not alter cellular rates of glucose oxidation but sensitized β-cells to glucose-induced changes in metabolic redox and insulin synthesis and release. In conclusion, chronic exposure to glibenclamide results in degranulation of a subpopulation of β-cells, which maintain an elevated protein and insulin synthetic activity irrespective of the presence of the drug and of glucose. Our study demonstrates that the in situ β-cell population also exhibits a functional heterogeneity that can vary with drug treatment. Glibenclamide induces degranulated β-cells with a sustained elevated basal activity that might increase the risk for hypoglycemic episodes., Previous studies (1-9) led us to propose that the normal pancreatic β-cell population exhibits intercellular differences that are functionally relevant, in particular for generating the normal dose-response curves to glucose. [...]

The development of islet cell transplantation as a cure for diabetes is limited by the shortage of human donor organs. Moreover, currently used grafts exhibit a marginal [beta]-cell mass with an apparently low capacity for [beta]-cell renewal and growth. Although duct-associated nonendocrine cells have often been suggested as a potential source for [beta]-cell production, recent work in mice has demonstrated the role of [beta]-cells in postnatal growth of the pancreatic [beta]-cell mass. The present study investigated whether the [beta]-cell mass can grow in implants that are virtually devoid of nonendocrine cells. Endocrine islet cells were purified from prenatal porcine pancreases (gestation >110 days) and implanted under the kidney capsule of nude mice. [beta]-Cells initially presented with signs of immaturity: small size, low insulin content, undetectable C-peptide release, and an inability to correct hyperglycemia. They exhibited a proliferative activity that was highest during posttransplant week 1 (2.6 and 5% bromodeoxyuridine [BrdU]-positive [beta]-cells 4 and 72 h posttransplant) and then decreased over 20 weeks to rates measured in the pancreas (0.2% BrdU-positive cells). [beta]-Cell proliferation in implants first compensated for [beta]-cell loss during posttransplant week 1 and then increased the [beta]-cell number fourfold between posttransplant weeks 1 and 20. Rates of [alpha]-cell proliferation were only shortly and moderately increased, which explained the shift in cellular composition of the implant ([beta]-cell 40 vs. 90% and [alpha]-cell 40 vs. 7% at the start and posttransplant week 20, respectively). [beta]-Cells progressively matured during the 20 weeks after transplantation, with a twofold increase in cell volume, a sixfold increase in cellular insulin content, plasma C-peptide levels of 1-2 ng/ml, and an ability to correct diabetes. They became structurally organized as homogenous clusters with their secretory vesicles polarized toward fenestrated capillaries. We concluded that the immature [beta]-cell phenotype provides grafts with a marked potential for [beta]-cell growth and differentiation and hence may have a potential role in curing diabetes. Cells with this phenotype can be isolated from prenatal organs; their presence in postnatal organs needs to be investigated., Islet cell transplantation has long been considered as a potential cure for diabetes (1,2). A transplantation protocol has been reported that has achieved a consistent insulin independence that has been [...]